Screening And Antitumor Studies On Novel Tryptanthrin Derivatives As Potent Inhibitors Of IDO

Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism ultimately leads to the production of the L-kynurenine and quinolinic acid (QUIN). IDO is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders and other diseases that are characterized by pathological tryptophan metabolism. IDO inhibition is proposed to have therapeutic potential. However, only a few structural classes are known to be IDO inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO inhibitor by the enzyme assay. Seventeen tryptanthrin derivatives were newly synthesized based on the structural modification and named as TQ series. The IDO inhibition activities of TQ series compounds were investigated, and enzyme kinetics constants were determined. As a result, thireen TQ series compounds were potent IDO inhibitors with higher activity than that of 1-MT, which is the commonly used IDO inhibitor. Besides, testing in a human HEK 293 cell line provided further evidence that TQ series compounds were potent inhibitors of IDO. It was exciting to find that two TQ compounds exhibited IDO inhibitory activity at a nanomolar level. In addition, TQ compounds dramatically augmented the proliferation of T cells in mixed lymphocyte reaction system. To investigate whether TQ compounds as IDO inhibitiors could reverse immune tolerance in vivo, we treated LLC (Lewis Lung Cancer) tumor-bearing Mice with IDO inhibitor (TQ-009 or TQ-004). The results showed that TQ-009 and TQ-004 significantly suppressed tumor growth and inhibited IDO activity. In our previous study, we found that CX series tryptanthrin derivatives were excellent IDO inhibitors, and compound CX-47 suppressed tumor growth. To further elucidate the possible direct effect of CX-47 on IDO, we carried out diphenylpicrylhydrazyl (DPPH) experiment and the surface plasmon resonance (SPR) experiment, it was concluded that CX-47 was directly applied to IDO molecular surface rather than inhibit IDO activity by oxidation, and the interaction equilibrium dissociation constant (KD) was 46.8 μM. In addition, we also preliminarily explored the potential of CX series tryptanthrin derivatives in the resistance to the tumor metastasis in vitro. Taken together, these results lead us to propose that the new tryptanthrin derivatives (TQ series andCX series) are attractive small molecule IDO inhibitors that may be used as antitumor agents.